Hypothesis and Evidence: Immune CellTherapy Might Yield Poor Outcomes in Patients with Diabetes

Abstract

Immune cell therapy has rapidly emerged as a novel strategy for cancer treatment, particularly with the development of chimeric antigen receptor (CAR) immunotherapy. However, the clinical efficacy of CAR-T, CAR-NK, and CAR-M therapies remains controversial in patients with metabolic diseases. Diabetes mellitus (DM) is one of the most prevalent metabolic diseases, with studies suggesting that patients with diabetes often develop chronic inflammation and a deteriorated tumor microenvironment (TME), leading to an increased prevalence of tumors. This review summarizes the pathways and molecular mechanisms underlying the deterioration of the tumor immune microenvironment in DM. It highlights the upregulation of reactive oxygen species, fatty acids, HIF-1 & VEGF, O-GlcNAc, TGF-β1, EGF, PGE2, and IGF-1 levels; downregulation of HIPK2 levels; and promotion of a pro-inflammatory bias in microRNA and exosome expression profiles. These changes downregulate immune cell activity through various mechanisms, including signal crosstalk, metabolism, and cellular interactions, thereby influencing the clinical efficacy of CAR-T, CAR-NK, and CAR-M therapies. Additionally, potential drugs targeting these pathways are proposed, offering new insights for improving the TME in patients with diabetes patients and enhancing